Despite the fact that hepatitis C virus (HCV) persists
chronically in about 80 percent of those infected, some liver cells remain free
of the virus even after many years. Now Sung Key Jang of Pohang University of
Science and Technology, South Korea, et al. explain that
paradox. During chronic HCV infection, a cellular protein, HMGB1, helps
restrain viral reproduction. That prevents HCV from sweeping the liver, and
results in a lower blood burden of virus than in the case of hepatitis B. This
first description of HMGB1-related responses triggered by HCV infection is
published in the September 2011 issue of the Journal of Virology.

The researchers show further that HCV-infected cells secrete
HMGB1 proteins into the extracellular milieu. There, these proteins trigger a
receptor on the cytoplasmic membrane, called TLR4, causing both an interferon
response, which fights the virus, and an inflammatory response.

Two different responses coming from the same receptor at the
same time is a common phenomenon. But that can make designing drugs all the
more complicated. Boosting the interferon response could vanquish the virus,
but the inflammatory response would be harmful. However, Jang says that it
might be possible to get the one response without the other. If HMGB1 in the
TLR4 receptor is like a hand that fits nicely in a glove, thus triggering both
responses, perhaps a drug could be fashioned which could fit a piece of the
receptor, like two fingers in a glove, thus triggering only the interferon
response. This is an unpublished hypothesis, says Jang, but one that his group
is working on.

In the paper, the researchers note that HMGB1 is a “danger”
signal. The Danger model of immunology, derived by Polly Matzinger of the
National Institute of Allergy and Infectious Disease, NIH, posits that immune
responses are initiated by signals from damaged cells. Rather than
distinguishing between “self” and “nonself,” as per conventional wisdom, the
Danger model suggests that when cells are stressed, injured, or killed (by
external forces rather than through so-called programmed cell death), they give
off alarm signals that activate the immune system to clear the damaging agents.

About 18 million people worldwide are infected with HCV.
That virus causes inflammation (hepatitis), massive death of liver cells
(cirrhosis), and hepatocellular carcinoma. Liver cancer, primarily
hepatocellular carcinoma, which is also caused by heptatitis B virus, is the
third leading cause of cancer deaths worldwide, and the ninth leading cause of
cancer deaths in the United States, according to Morbidity and Mortality Weekly
Report http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5917a3.htm/.